A Safety and Dose-finding Study of PRL-02 Depot in Men With Advanced Prostate Cancer

Inclusion Criteria:

• Histological evidence of adenocarcinoma of the prostate

• Phase 1a Dose Escalation Groups A and B: participants must have one of the followingdocumented conditions:

• mCSPC (must have documentation by positive bone scan [for bone disease] ormetastatic lesions on computed tomography [CT] or magnetic resonance imaging [MRI] scan [for soft tissue])

• nmCSPC with biochemical relapse of prostate cancer

• mCSPC with oligometastatic prostate cancer (e.g., positron emission tomographypositive)

• mCRPC (must have documentation by positive bone scan [for bone disease] ormetastatic lesions on CT or MRI scan [for soft tissue])

• NOTE: For participants in the Dose Escalation Cohorts (including backfill) ateach of the dose levels up to approximately 10 participants with ARPI-naïvemCRPC who have not received prior treatment with an ARPI (e.g., abirateroneacetate, enzalutamide, apalutamide, darolutamide) will be enrolled.

• Phase 1a Dose Escalation Groups A and B: participants with mCRPC must have evidenceof disease progression defined as one or more of the following:

• Evidence of radiographic progression of disease following the most recentprostate cancer treatment, defined as progressive disease on CT/MRI per RECISTv1.1 or on a bone scan per PCWG3.

• PSA progression defined as the following:

• PSA nadir is defined as the lowest PSA during or after the most recent treatment.PSA progression is defined as an increased PSA of at least 25% and ≥1 ng/mL abovethe nadir confirmed by at least 2 measurements with a minimum of 1 week apart, andwith at least 1 of the measurements within 90 days prior to screening.

• Participants with nmCSPC and biochemical recurrence, who had a radical prostatectomy (with or without radiotherapy) as the primary treatment for prostate cancer, musthave a screening PSA ≥1 ng/mL. Participants with nmCSPC and biochemical recurrencewho had radiotherapy only, as primary treatment for prostate cancer, must have ascreening PSA ≥2 ng/mL above the nadir.

• Phase 1b Expansion Groups D and E: participants must have mCRPC Participants inGroup D must have received prior treatment with abiraterone acetate, but must nothave received treatment with other ARPIs (enzalutamide, apalutamide ordarolutamide). Participants in Group E must have received prior treatment with only 1 of the following ARPIs: enzalutamide, apalutamide or darolutamide. Participants inboth Groups D and E must have documented evidence of progression with one or more ofthe following:

• Evidence of radiographic progression of disease following the most recentprostate cancer treatment, defined as progressive disease on CT/MRI per RECISTv1.1 or on a bone scan per PCWG3. Disease spread that is limited to theregional pelvic lymph nodes does not qualify as radiographic progression.

• PSA progression defined as the following:

• PSA nadir is defined as the lowest PSA during or after the most recenttreatment. PSA progression is defined as an increased PSA of at least 25% and ≥1 ng/mL above the nadir confirmed by at least 2 measurements with a minimum of 1 week apart, and with at least 1 of the measurements within 90 days prior toscreening.

• Participants with mCRPC must have undergone bilateral orchiectomy or receivedconcurrent GnRH agonist or antagonist therapy for at least 6 weeks prior to thefirst dose of study drug.

• Participants with mCSPC or nmCSPC with biochemical recurrence should have received <6 months of ADT with a GnRH agonist or antagonist or have a history of bilateralorchiectomy (i.e., surgical or medical castration) within 6 months prior to Day 1.Castration therapy (i.e., medical or surgical) must have been started at least 14days prior to Cycle 1 Day 1 and participants should have no radiographic evidence ofdisease progression or rising PSA levels after starting ADT and prior to Cycle 1 Day

• A serum testosterone level <50 ng/dL at screening (for mCRPC participants only)

• Adequate muscle mass for an i.m. injection

• An ECOG PS of 0 or 1

• Adequate bone marrow reserve defined as:

• Absolute neutrophil count (ANC) ≥1500/µL

• Platelet count ≥100,000/µL

• Hemoglobin ≥9 gm/dL

• Adequate renal function defined as a serum creatinine ≤1.5 × upper limit of normal (ULN) for the reference laboratory or a calculated creatinine clearance ≥50 mL/minas determined by a validated algorithm for calculating creatinine clearance

• Adequate hepatic function, defined as alanine aminotransferase (ALT) and aspartateaminotransferase (AST) ≤2.5 × ULN and total bilirubin ≤1.5 × ULN. Exception forelevated bilirubin secondary to Gilbert's disease. Confirmation of Gilbert'sdiagnosis requires: elevated unconjugated (indirect) bilirubin values; normalcomplete blood count in previous 12 months, blood smear, and reticulocyte count;normal aminotransferases and alkaline phosphatase in previous 12 months.

• Serum albumin ≥3 gm/dL and serum potassium ≥3.5 mEq/L

• Participants who are non-sterile and who are heterosexually active with a femalepartner of childbearing potential must be willing to use a highly effective means ofcontraception, such as a male condom plus spermicide, from the time of screening,throughout the total duration of the drug treatment, and until 12 weeks after thefinal dose of PRL-02 or enzalutamide (Group H).

• Participant is able to comply with study requirements throughout the study.

The Following Inclusion Criteria Apply to Dose Escalation Group H Only

• Participants must have one of the following documented conditions:

• mCSPC (must have documentation of a positive PMSA-PET or positive bone scan [for bone disease] or metastatic lesions on CT or MRI scan [for soft tissue])

• mCRPC (must have documentation of a positive PMSA-PET or positive bone scan [for bone disease] or metastatic lesions on CT or MRI scan [for soft tissue])

• NOTE: For participants in the Dose Escalation Cohorts (including backfill) ateach of the dose levels, the Sponsor may elect to enroll up to 10 participantswith ARPI-naïve mCRPC who have not received prior treatment with an ARPI (e.g.,abiraterone acetate, enzalutamide, apalutamide, darolutamide).

• Participants with mCRPC must have evidence of disease progression defined as one ormore of the following:

• Evidence of radiographic progression of disease following the most recentprostate cancer treatment, defined as progressive disease on CT/MRI per RECISTv1.1 or on a bone scan per PCWG3.

• PSA progression defined as the following:

• PSA nadir is defined as the lowest PSA during or after the most recent treatment.PSA progression is defined as an increased PSA of at least 25% and ≥1 ng/mL abovethe nadir confirmed by at least 2 measurements with a minimum of 1 week apart, andwith at least 1 of the measurements within 90 days prior to screening.

• Participant is able to swallow enzalutamide capsules whole.

Exclusion Criteria:

• Known active central nervous system (CNS) metastases. Note: Participants with CNSmetastases that have been treated with surgery and/or radiation therapy, who are offpharmacologic doses of glucocorticoids, and who are neurologically stable areeligible.

• Impending bone fracture due to bone metastases

• Has a known additional malignancy beyond prostate cancer that required activetreatment with the exception of any of the following:

• Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin,or in situ carcinoma of any type

• Adequately treated Stage I cancer from which the participant is currently inremission and has been in remission for ≥2 years

• Any other cancer from which the participant has been disease-free for ≥5 years

• Clinically significant cardiac disease, defined as any of the following:

• Clinically significant cardiac arrhythmias including bradyarrhythmia which arepoorly controlled.

• Congenital long QT syndrome

• QT interval corrected by Fridericia's formula (QTcF) ≥450 msec at screening (based on average of triplicate ECGs at baseline). If the QT interval correctedfor heart rate intervals (QTc) is prolonged in a participant with a pacemakeror bundle branch block, the participant may be enrolled in the study ifconfirmed by the Medical Monitor.

• History of clinically significant cardiac disease or congestive heart failuregreater than New York Heart Association (NYHA) Class II or left ventricularejection fraction measurement of <50% at baseline. Participants must not haveunstable angina (symptoms at rest) or new-onset angina within the last 3 monthsor myocardial infarction within the past 6 months [NYHA Classification 2014].

• Uncontrolled hypertension, defined as systolic blood pressure (BP) >160 mmHg ordiastolic BP >100 mmHg which has been confirmed by 2 successive measurementsdespite optimal medical management.

• Arterial or venous thrombotic or embolic events such as cerebrovascularaccident (including transient ischemic attacks), deep vein thrombosis, orpulmonary embolism within the 3 months before start of study medication (exceptfor adequately treated catheter-related venous thrombosis occurring >1 monthbefore the start of study medication).

• Received an investigational drug within 4 weeks or 5 half-lives (whichever isshorter) of the first dose of study drug.

• Received chemotherapy within 2 weeks or 5 half-lives (whichever is shorter) of thefirst dose of study drug.

• Additional criteria: ARPI-naïve mCRPC participants enrolled in the DoseEscalation Cohorts (including backfill) must not have received priorchemotherapy in the mCRPC setting (prior receipt of chemotherapy in the mCSPCsetting is allowed, if received at least 2 weeks or 5 half-lives prior to thefirst dose of study drug).

• Any unresolved NCI CTCAE criteria v5.0 Grade >2 toxicity from previous anticancertherapy at the Screening visit. Note: Participants receiving ongoing hormonereplacement therapy for endocrine immune-related AEs without clinical symptoms willnot be excluded.

• Has not recovered from recent major surgery or trauma

• Received a blood transfusion within 2 weeks of the first dose of study drug

• History of impaired pituitary or adrenal gland function (e.g., Addison's disease,Cushing's syndrome)

• Prior treatment with abiraterone acetate, orteronel. Exception: participants inPhase 1b Expansion Group D will have received prior abiraterone acetate, andparticipants in Group H may have received prior treatment with abiraterone acetate.

• Current treatment with systemic ketoconazole or any other CYP17 inhibitor.Participants who have received systemic ketoconazole or any other CYP17 inhibitormust have discontinued these agents ≥4 weeks prior to the first dose of study drug.

• Prior systemic treatment with an azole drug (e.g., fluconazole, itraconazole) within 4 weeks of first dose of study drug.

• Prior treatment with estrogens within 12 weeks of the first dose of study drug

• Need for systemic glucocorticoids greater than replacement doses; the use oftopical, intraocular, inhalational, intranasal, or intra-articular glucocorticoidsis permitted.

• Prior use of any herbal products that could decrease PSA levels (e.g., saw palmetto)within 4 weeks of the first dose of study drug. Participants must agree not to usesuch herbal products during study participation.

• Use of biotin (i.e., vitamin B7) or supplements containing biotin higher than thedaily adequate intake of 30 µg [NIH-ODS 2022]. Note: Participants who switch from ahigh dose to a dose of 30 µg/day or less prior to first dose of study drug areeligible for study entry.

• Required concomitant use of strong inducers of CYP3A4, except for enzalutamide givenas study drug in Group H

• Known hypersensitivity to PRL-02, abiraterone, abiraterone decanoate, prednisone, ordexamethasone or any of their excipients or components.

• Has jaundice or known current active liver disease from any cause, includinghepatitis A (hepatitis A virus immunoglobulin M [IgM] positive), hepatitis B (hepatitis B virus surface antigen [HBsAg] positive, confirmed by polymerase chainreaction [PCR]), or hepatitis C (hepatitis C virus [HCV] antibody positive,confirmed by HCV ribonucleic acid)

• Hemoglobin A1c (HbA1c) >10% in participants previously diagnosed with diabetesmellitus. HbA1c >8% in participants whose diabetes mellitus is previouslyundiagnosed. (Excluded participants may be rescreened after referral and evidence ofimproved control of their condition).

• Uncontrolled infection with human immunodeficiency virus (HIV)+. Exception:participants with well-controlled HIV (e.g., CD4 >350/mm3 and undetectable viralload) are eligible.

• Body mass index >40 kg/m2

The Following Exclusion Criteria Apply to Dose Escalation Group H Only

• Clinically significant cardiac disease, defined as any of the following:

• NYHA class III or IV congestive heart failure or a history of NYHA class III orIV congestive heart failure, unless a screening echocardiogram or multigatedacquisition scan performed within 3 months before the randomization datedemonstrates a left ventricular ejection fraction of ≥45%

• History of Mobitz II second-degree or third-degree heart block without apermanent pacemaker in place

• Hypotension as indicated by systolic BP <86 mm Hg at screening

• Bradycardia as indicated by a heart rate of ≤45 beats per minute on thescreening ECG

• Participant has a history of seizure or any condition that may predispose toseizure.

• Use or required use of any prohibited medication.

• Participant has a gastrointestinal disorder affecting absorption.

• Participant has shown hypersensitivity reaction to the active pharmaceuticalingredient or any of the study capsule components, including Labrasol®, butylatedhydroxyanisole, and butylated hydroxytoluene.